No Through Road

WHAT WOULD YOU DO if you were in your car on the way to a family celebration and found yourself trapped in a traffic jam? A generation ago, you probably would have pulled out a map. Today, you’d probably rely on GPS or a smartphone to see your options. And as you selected a route around the blockade, you’d be doing precisely what cancer cells have done since time immemorial.

That’s because a cancer cell is equipped with something akin to a real-time Google Street View car, allowing the rogue cell to identify alternate routes it can take or build when a cancer drug disrupts or blocks its primary path of survival. What’s more, each time a cancer cell learns how to get past one treatment, it becomes better prepared to outsmart another. The medical term for a cancer cell’s ability to outmaneuver a cancer therapy is drug resistance, and it is ultimately responsible for many of the cancer deaths that occur.

Overcoming drug resistance is not a new goal, but over the past five years, as targeted therapies have seen more success, ideas about how to tackle resistance have begun changing. By tracking how cancer cells respond when they face a barricade, scientists may finally be able to learn how to outfox them.

Anticipating the Enemy

The scientific advances that led to targeted therapies, which block a specific growth mechanism inside a cancer cell, have opened up new ways of thinking about drug resistance. “Insights into targeted therapies have come much more quickly” than they did for chemotherapy, when it comes to understanding drug resistance, says Charles Sawyers, a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York City. “By definition, targeted therapies have targets, so when resistance develops, the natural first question is whether there is some change in the target. … So while it can sound discouraging that you make a targeted therapy and the tumor is outsmarting the drug, the good news is that we know the enemy and we know what the likely first line of defense will be—and we can anticipate it.”

That’s precisely what the researchers in Sawyers’ laboratory at Memorial Sloan-Kettering are trying to do: predict what a cancer cell will do next, and then figure out a drug that will block its end run. Their first success was in chronic myeloid leukemia (CML), a cancer of the white blood cells. Sawyers’ laboratory had played a critical role in the development of Gleevec (imatinib), the first drug developed specifically to block a molecule in a cancer cell—in this case a protein called bcr-abl—known to fuel the cell’s growth.

Gleevec transformed CML from a death sentence into a manageable illness, catapulting the drug to the cover of Time magazine in 2001. Then, a problem emerged. In some patients, the drug stopped working—the cancer had identified the blockade and found a detour. Enter Sawyers. Using the same technology that led to Gleevec, his team soon found that the resistant cancer cells had developed mutations that changed the shape of the bcr-abl protein that Gleevec targeted. This discovery led to Sprycel (dasatinib), a targeted therapy granted accelerated approval in 2006 that is given to patients whose cancer cells are no longer responding to treatment because they have learned how to get past the barricade that Gleevec puts in their way.

Sawyers is now using a similar technology to identify the tricks that metastatic prostate cancer uses to get around the androgen receptor antagonist Xtandi (enzalutamide), which was approved in August 2012 to treat men who had already been on the chemotherapy drug Taxotere (docetaxel). Sawyers’ team began developing Xtandi in 2004, and he started thinking about how cancer cells would learn to get around it even before the drug was given to patients.

“The same models we used to demonstrate the benefit of the drug showed that if we treat cells in [laboratory dishes] or mice, we can develop resistance,” he says. His team then looked at cancer cells collected from men with prostate cancer who were taking Xtandi and found that they were starting to develop similar new pathways around the drug. So far, there have only been a limited number of patients to look at, says Sawyers, and it’s too early to tell how commonly cancer cells are using this detour around Xtandi. But he’s “fairly certain” that it will prove to be an important way in which cancer cells can circumvent the drug. “And,” he adds, “because it is one that can be acted upon now—not tomorrow—with existing drugs, it points the way to what the next generation of these drugs should look like.”

Overcoming Adaptation

In some instances, a cell’s success in getting past the blockade can be chalked up to epigenetics, the process by which genes change how they function. “Epigenetics is the phenomena of how we adapt to life,” explains Pamela N. Munster, an oncologist at the University of California, San Francisco. “You are born with a set of genes that cannot be changed … but your genes can adapt to the environment.” And just as the body of a person facing starvation learns how to adapt to fewer nutrients, says Munster, “tumor cells learn how to adapt, too.” They also know how to package this knowledge and put it into an epigenetic tag—which specifies this adaptation—on the DNA they pass to their daughter cells. In this way, says Munster, “the cell isn’t just passing on the ability to make certain proteins, it is passing on resistance.”

Munster watched this happen while she was trying to learn why, over time, estrogen receptor-positive breast cancer cells stopped responding to the hormone therapy tamoxifen. What her team saw, she says, is that “the estrogen receptor modifies itself” so that it learns to become independent of tamoxifen.

Discovering that these changes were happening in the cells’ DNA was an important new clue to understanding how this type of resistance developed. It also allowed Munster’s team to consider investigating whether a histone deacetylase (HDAC) inhibitor—a type of drug used to treat epilepsy, and which causes changes to occur in a cell’s DNA—might disrupt the breast cancer cell’s progress down its new path of resistance. The study showed that using the HDAC inhibitor on its own after tamoxifen resistance developed wasn’t effective at all. But when the HDAC inhibitor was given along with tamoxifen, the researchers found that the cancer cells no longer became resistant—instead, they died. Explains Munster, “the inhibitor removed the resistance pathway the cell put in place to get around the tamoxifen” by removing the epigenetic tag.

Laboratory studies suggest that HDAC inhibitors also should be able to reverse resistance to other targeted drugs in other types of cancers—and clinical trials are currently exploring that possibility. Scientists already know, though, that the drugs won’t work for everybody. Only about 60 percent of the population has normal cells that would react to an HDAC inhibitor. “And these are the only patients whose tumors will respond,” says Munster. “So what we are working on now is a way to figure out who these patients are.”

Also on the table: determining new measures of effectiveness, beyond tumor shrinkage, when evaluating the effectiveness of drugs that stop resistance. “HDAC inhibitors may not necessarily shrink tumors,” says Munster, “but they may keep them from progressing. And if the tumor stays under control and doesn’t grow back, then that is an important piece of information that would tell us how and if the drug is working.” And it’s an important benefit to patients as well, adds Munster.

Observing Resistance

Six years ago, Apostolia Maria Tsimberidou, a hematologist and oncologist at the University of Texas M. D. Anderson Cancer Center in Houston, was primarily interested in studying cancer cells that had become resistant to chemotherapy. Now, her focus has shifted to investigating ways to overcome or prevent resistance to targeted therapies.

Blood cancers provide fertile ground for testing resistance theories, in part because the cancer cells are easily obtainable. Now, as they conduct clinical trials to study targeted therapies, Tsimberidou and her colleagues routinely “perform biopsies every one or two months … so that we can detect resistance at the molecular level early on, and then adjust treatment accordingly,” she says.

Identifying the molecular changes occurring in solid tumors that help them become resistant is more challenging. For one, notes Tsimberidou, obtaining a tumor sample from a solid tumor typically requires performing an image-guided biopsy, and not all solid tumor sites are equally accessible. In addition, she says, studies have found that cancer cells removed from the original tumor—in, say, the kidney—may not be the same as those found at the sites of metastases. “At the end of the day, though,” Tsimberidou says, “when we order a biopsy, we have to get the cells from the site that is safest” to get to.

A question underlying all of this work is whether some people’s cancers are inherently better at becoming resistant. One potential factor: how early the cancer is found. A late-stage tumor has had time to develop lots of pathways of resistance. These tumors, notes Sawyers, “have so many tumor cells that their probability of having a cell that is already resistant to treatment is higher mathematically.” In addition, he says, “later-stage tumors tend to be more genetically unstable so they can evolve more rapidly to get around drugs.” That’s why, he says, it’s easier for the cancer cells in someone with late-stage CML to become resistant to Gleevec than it is for those in someone whose cancer is at an early stage. And the difference between the learning curves of the early stage and late-stage tumors as they try to outwit the drug is vast. As Sawyers notes, “It’s a difference of months versus years.”

Metastatic melanoma provides another insightful example. Until recently, no treatments worked to stop the disease from continuing to spread. “Now, in that disease we are seeing that a combination approach [that uses targeted therapies and immunotherapies] is improving the length of time until resistance occurs,” Sawyers says.

This suggests it may not be that metastatic melanoma is inherently better than other cancers at becoming resistant, but rather that researchers are only now discovering the right ways to put barriers in its path that it can’t bypass. The next step is figuring out how melanoma cells get around these new drugs—and blocking those pathways, too.

For that to happen in melanoma and other cancers, a focus on resistance needs to be part and parcel of the development of every new cancer therapy—from the beginning. This could mean, says Tsimberidou, “starting with a targeted agent and then seeing if using it on and off will prevent the development” of those pathways or “whether we should combine drugs [that target] different pathways early on so we are hitting multiple pathways at once simultaneously, or if tumors are less likely to become resistant if we use the drugs sequentially.” Phase I trials exploring these approaches are now under way.

All of this work will require close observation of how a tumor finds and creates its new pathways at specific times. To find the answers, says Tsimberidou, “we have to allow patients’ tumors to teach us.”

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